This invention relates to a novel series of quinoxaline-1,4-dioxides which are useful as antibacterial agents. They are effective, for instance, as urinary tract antiseptics, systemic antiinfectives, animal growth promotants and agents for the control of chronic respiratory disease in turkeys and the improvement of feed efficiency in animals. In particular, it relates to esters formed between various 3-(.alpha.-hydroxymethyl)quinoxaline-1,4-dioxides and various acids having certain hyroxyphenyl groups at the .omega.-position.
The use of quinoxaline-1,4-dioxides as antibacterial agents is known in the art. For instance, U.S. Pat. No. 3,344,022 discloses a series of compounds of the structure ##SPC2##
Wherein
R.sub.1 is selected from the group consisting of hydrogen, alkyl of up to 10 carbon atoms, .alpha.-hydroxy lower alkyl, .alpha.-lower alkanoyloxy lower alkyl, .alpha.-lower alkoxy lower alkyl, and formyl; PA1 R.sub.2 is selected from the group consisting of alkyl of up to 10 carbon atoms, lower alkanoyl, .alpha.-hydroxy lower alkyl, formyl, .alpha.-lower alkanoyloxy lower alkyl, and .alpha.-lower alkoxy lower alkyl; and PA1 X.sub.1, x.sub.2, x.sub.3 and X.sub.4 are each selected from the group consisting of hydrogen and lower alkyl, which are effective in maintaining weight gain and feed consumption of poultry in the presence of chronic respiratory disease and in controlling chronic respiratory disease, and in accelerating growth and improving feed efficiency of animals. Many of the compounds of the above-mentioned U.S. Patent are used as starting materials in the preparation of the compounds of the present invention. PA1 R.sub.1 is hydrogen, lower alkyl, lower alkoxy, hydroxy or an acyloxy moiety of a lower aliphatic carboxylic acid; PA1 R.sub.2 is hydrogen, an aliphatic moiety or an aliphatic moiety substituted by hydroxy, lower alkoxy, carbalkoxy, monoalkylamino or dialkylamino; PA1 R.sub.3 is hydrogen, an aliphatic moiety or an aliphatic moiety substituted by hydroxy, lower alkoxy, carbalkoxy, monoalkylamino or dialkylamino, or R.sub.2 and R.sub.3 are each lower alkyl linked together with the amide nitrogen to form a 5-, 6- or 7-membered heterocyclic ring or R.sub.2 and R.sub.3 are each lower alkyl linked together with an amide nitrogen to form a 5-, 6- or 7-membered heterocyclic ring having N or O as a second heteroatom; and PA1 R.sub.4 is hydrogen, lower alkyl or substituted or unsubstituted phenyl. U.S. Pat. No. 3,558,624 also describes a series of 2-carboxamides, some of which are structurally isomeric with the above-mentioned compounds, of the structure ##SPC4## PA1 R.sub.1 is hydrogen, lower alkyl, lower alkoxy or chlorine; PA1 R.sub.2 is hydrogen or a straight or branched chain alkyl radical unsubstituted or substituted by hydroxy, lower alkoxy, acyloxy or mono- or dialkylamino; PA1 R.sub.3 is hydrogen or a straight or branched chain alkyl radical unsubstituted or substituted by hydroxy, lower alkoxy, acyloxy or mono- or dialkylamino or, when R.sub.2 is hydroxy, R.sub.3 is cyclohexyl; or PA1 R.sub.2 and R.sub.3 together with the amide nitrogen atom form a 5- 6-membered ring, PA1 R.sub.4 is alkyl, halogen substituted alkyl, phenyl or hydroxy, methoxy or acetoxy substituted phenyl, and PA1 X is oxygen or sulfur. PA1 X is selected from the group consisting of a single bond, lower n-alkylene, and --(CH.sub.2).sub.p --CH=CH--(CH.sub.2).sub.q -- wherein p and q have integral values from zero to four with the proviso that p plus q is less than or equal to four; PA1 A is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, lower alkoxy, fluorine, chlorine, bromine, iodine, cyano and trifluoromethyl; and PA1 R is selected from the group consisting of hydrogen lower alkanoyl and .alpha.-hydroxy lower alkyl are useful as antibacterial agents and growth and feed efficiency promoters in animals.
The use of esters of various 3-hydroxymethyl quinoxaline-1,4-dioxides is known in the art. For instance, U.S. Pat. No. 3,369,400 describes a series of 2-carboxamides of the structure ##SPC3##
Wherein
in which
Though these carboxamides appear from in vitro tests to be valuable antibacterial agents, it has been found that many of them either are ineffective in test animals against certain target diseases, particularly pasturellosis, salmonellosis and swine dysentery or must be used with extreme caution. In contrast, the compounds of the present invention are safer and show a high in vivo activity against a number of serious veterinary diseases. Therefore, it appears that the prior art on 3-carboxylic acid esters of quinoxaline dioxides is of little value as an indicator of the operative structure-activity relationships in this class of antibacterial agents.